Mouse  lifespan  extended  up  to  24%  with  a  single  treatment  

 

CNIO  SCIENTISTS  SUCCESSFULLY  TEST  THE  FIRST  GENE  THERAPY   AGAINST  AGEING-­‐ASSOCIATED  DECLINE    

 

• The  first  anti-­‐ageing  therapy  potentially  applicable  in  humans  that  acts   directly  on  the  genes       • Published  today  in  EMBO  Molecular  Medicine,  the  study  consists  of  inducing   cells  to  express  telomerase,  the  enzyme  which  –  metaphorically  –  slows   down  the  biological  clock   • The  research  provides  a  “proof-­‐of-­‐principle”  that  this  “feasible  and  safe”   approach  can  effectively  “improve  healthspan”,  in  the  words  of  a   commentary  published  in  the  same  journal  

  Madrid  (Spain),  May  15th,  2012.-­‐  A  number  of  studies  have  shown  that  it  is  possible   to  lengthen  the  average  life  of  individuals  of  many  species,  including  mammals,  by   acting   on   specific   genes.   To   date,   however,   this   has   meant   altering   the   animals’   genes   permanently   from   the   embryonic   stage   –   an   approach   impracticable   in   humans.  Researchers  at  the  Spanish  National  Cancer  Research  Centre  (CNIO),  led  by   its  director  María  Blasco,  have  proved  that  mouse  lifespan  can  be  extended  by  the   application  in  adult  life  of  a  single  treatment  acting  directly  on  the  animal’s  genes.   And   they   have   done   so   using   gene   therapy,   a   strategy   never   before   employed   to   combat  ageing.  The  therapy  has  been  found  to  be  safe  and  effective  in  mice.       The  results  are  published  today  in  the  journal  EMBO  Molecular  Medicine.  The  CNIO   team,   in   collaboration   with   Eduard   Ayuso   and   Fátima   Bosch   of   the   Centre   of   Animal   Biotechnology  and  Gene  Therapy  at  the  Universitat  Autònoma  de  Barcelona  (UAB),   treated   adult   (one-­‐year-­‐old)   and   aged   (two-­‐year-­‐old)   mice,   with   the   gene   therapy   delivering  a  “rejuvenating”  effect  in  both  cases,  according  to  the  authors.       Mice  treated  at  the  age  of  one  lived  longer  by  24%  on  average,  and  those  treated  at   the   age   of   two,   by   13%.   The   therapy,   furthermore,   produced   an   appreciable   improvement   in   the   animals’   health,   delaying   the   onset   of   age-­‐related   diseases   –  

like  osteoporosis  and  insulin  resistance  –  and  achieving  improved  readings  on  ageing   indicators  like  neuromuscular  coordination.       The   gene   therapy   utilised   consisted   of   treating   the   animals   with   a   DNA-­‐modified   virus,  the  viral  genes  having  been  replaced  by  those  of  the  telomerase  enzyme,  with   a   key   role   in   ageing.   Telomerase   repairs   the   extremes   of   chromosomes,   known   as   telomeres,  and  in  doing  so  slows  the  cell’s  and  therefore  the  body’s  biological  clock.   When   the   animal   is   infected,   the   virus   acts   as   a   vehicle   depositing   the   telomerase   gene  in  the  cells.     This  study  “shows  that  it  is  possible  to  develop  a  telomerase-­‐based  anti-­‐ageing  gene   therapy   without   increasing   the   incidence   of   cancer”,   the   authors   affirm.   “Aged   organisms  accumulate  damage  in  their  DNA  due  to  telomere  shortening,  [this  study]   finds  that  a  gene  therapy  based  on  telomerase  production  can  repair  or  delay  this   kind  of  damage”,  they  add.     'Resetting’  the  biological  clock     Telomeres  are  the  caps  that  protect  the  end  of  chromosomes,  but  they  cannot  do  so   indefinitely:   each   time   the   cell   divides   the   telomeres   get   shorter,   until   they   are   so   short  that  they  lose  all  functionality.  The  cell,  as  a  result,  stops  dividing  and  ages  or   dies.  Telomerase  gets  round  this  by  preventing  telomeres  from  shortening  or  even   rebuilding  them.  What  it  does,  in  essence,  is  stop  or  reset  the  cell’s  biological  clock.       But  in  most  cells  the  telomerase  gene  is  only  active  before  birth;  the  cells  of  an  adult   organism,  with  few  exceptions,  have  no  telomerase.  The  exceptions  in  question  are   adult  stem  cells  and  cancer  cells,  which  divide  limitlessly  and  are  therefore  immortal   –   in   fact   several   studies   have   shown   that   telomerase   expression   is   the   key   to   the   immortality  of  tumour  cells.       It   is   precisely   this   risk   of   promoting   tumour   development   that   has   set   back   the   investigation  of  telomerase-­‐based  anti-­‐ageing  therapies.       In   2007,   Blasco’s   group   proved   that   it   was   feasible   to   prolong   the   lives   of   transgenic   mice,   whose   genome   had   been   permanently   altered   at   the   embryonic   stage,   by   causing  their  cells  to  express  telomerase  and,  also,  extra  copies  of  cancer-­‐resistant   genes.  These  animals  live  40%  longer  than  is  normal  and  do  not  develop  cancer.       The  mice  subjected  to  the  gene  therapy  now  under  test  are  likewise  free  of  cancer.   Researchers  believe  this  is  because  the  therapy  begins  when  the  animals  are  adult   so   do   not   have   time   to   accumulate   sufficient   number   of   aberrant   divisions   for   tumours  to  appear.    

Also   important   is   the   kind   of   virus   employed   to   carry   the   telomerase   gene   to   the   cells.   The   authors   selected   demonstrably   safe   viruses   that   have   been   successfully   used   in   gene   therapy   treatment   of   haemophilia   and   eye   disease.   Specifically,   they   are  non-­‐replicating  viruses  derived  from  others  that  are  non-­‐pathogenic  in  humans.     This  study  is  viewed  primarily  as  “a  proof-­‐of-­‐principle  that  telomerase  gene  therapy   is  a  feasible  and  generally  safe  approach  to  improve  healthspan  and  treat  disorders   associated   with   short   telomeres”,   state   Virginia   Boccardi   (Second   University   of   Naples)   and   Utz   Herbig   (New   Jersey   Medical   School-­‐University   Hospital   Cancer   Centre)  in  a  commentary  published  in  the  same  journal.       Although   this   therapy   may   not   find   application   as   an   anti-­‐ageing   treatment   in   humans,   in   the   short   term   at   least,   it   could   open   up   a   new   treatment   option   for   ailments   linked   with   the   presence   in   tissue   of   abnormally   short   telomeres,   as   in   some  cases  of  human  pulmonary  fibrosis.     More  healthy  years     As  Blasco  says,  “ageing  is  not  currently  regarded  as  a  disease,  but  researchers  tend   increasingly  to  view  it  as  the  common  origin  of  conditions  like  insulin  resistance  or   cardiovascular   disease,   whose   incidence   rises   with   age.   In   treating   cell   ageing,   we   could  prevent  these  diseases”.       With   regard   to   the   therapy   under   testing,   Bosch   explains:   “Because   the   vector   we   use   expresses   the   target   gene   (telomerase)   over   a   long   period,   we   were   able   to   apply   a   single   treatment.   This   might   be   the   only   practical   solution   for   an   anti-­‐ageing   therapy,  since  other  strategies  would  require  the  drug  to  be  administered  over  the   patient’s  lifetime,  multiplying  the  risk  of  adverse  effects”.      

 

Maria  A.  Blasco  and  Bruno  M.  Bernardes  de  Jesus  (co-­‐ author)  in  the  CNIO  building  in  Madrid.      

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